Doctoral course in the Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences

  • Professor: TAKAMURA, Toshinari, MD & PhD
  • Associate Professor: MISU, Hirofumi, MD & PhD

Nature ascertains a pivotal role for every biological system like clockwork and is unlikely to maintain systems that are detrimental for survival. Any pathway and molecule that causes illness must also have a meaningful role. Overnutrition disrupts inter-organ networks to keep energy homeostasis governed by the liver. Our group has identified key pathways and molecules (hepatokine world) through comprehensive gene expression analyses of tissue and cell samples from humans and model animals. Through functional analyses of these diagnostic/therapeutic targets, we aim to create medical systems for preclinical diagnosis and preemptive/tailor-made medicine.

Research projects

  1. Molecular pathology and clinical research in diabetes/obesity and its complications
  2. Cross-talks among glucose-, protein-, and lipid-metabolism pathways to keep energy homeostasis
  3. Hepatokines (liver-derived hormones) and inter-organ networks
  4. Histological course and molecular pathology of non-alcoholic fatty liver disease (NAFLD)
  5. Molecular epidemiology aiming for precision medicine against lifestyle-related diseases such as type 2 diabetes and obesity

Pathology of type 2 diabetes caused by a liver-derived hormone hepatokine

The liver plays a role as an endocrine organ to produce functional hepatokines and thereby mediates fatty liver-associated systemic pathology. We discovered a liver-derived hormone selenoprotein P that causes multi-signal resistances via reductive stress leading to pathology of type 2 diabetes such as insulin resistance, angiogenesis resistance, exercise resistance, and insulin secretory failure.

Key publications

  1. Misu H, Takayama H, Saito Y, Mita Y, Kikuchi A, Ishii KA, Chikamoto K, Kanamori T, Tajima N, Lan F, Takeshita Y, Honda M, Tanaka M, Kato S, Matsuyama N, Yoshioka Y, Iwayama K, Tokuyama K, Akazawa N, Maeda S, Takekoshi K, Matsugo S, Noguchi N, Kaneko S, Takamura T*. Deficiency of the hepatokine selenoprotein P increases responsiveness to exercise in mice through upregulation of reactive oxygen species and AMP-activated protein kinase in muscle. Nat Med 23:508-516, 2017
  2. Mita Y, Nakayama K, Inari S, Nishito Y, Yoshioka Y, Sakai N, Sotani K, Nagamura T, Kuzuhara Y, Inagaki K, Iwasaki M, Misu H, Ikegawa M, Takamura T, Noguchi N, Saito Y. Selenoprotein P-neutralizing antibodies improve insulin secretion and glucose sensitivity in type 2 diabetes mouse models. Nat Commun 8:1658, 2017
  3. Misu H, Takamura T* (co-first author), Takayama H, Hayashi H, Matsuzawa-Nagata N, Kurita S, Ishikura K, Ando H, Takeshita Y, Ota T, Sakurai M, Yamashita T, Mizukoshi E, Yamashita T, Honda M, Miyamoto K, Kubota T, Kubota N, Kadowaki T, Kim HJ, Lee IK, Minokoshi Y, Saito Y, Takahashi K, Yamada Y, Takakura N, Kaneko S. A liver-derived secretory protein, selenoprotein P, causes insulin resistance. Cell Metab 12:483-95, 2010
  4. Ishikura K, Misu H, Kumazaki M, Takayama H, Matsuzawa-Nagata N, Tajima N, Chikamoto K, Lan F, Ando H, Ota T, Sakurai M, Takeshita Y, Kato K, Fujimura A, Miyamoto K, Saito Y, Kameo S, Okamoto Y, Takuwa Y, Takahashi K, Kidoya H, Takakura N, Kaneko S, Takamura T*. Selenoprotein P as a diabetes-associated hepatokine that impairs angiogenesis by inducing VEGF resistance in vascular endothelial cells. Diabetologia 57:1968-76, 2014
  5. Oo SM, Misu H, Saito Y, Tanaka M, Kato S, Kita Y, Takayama H, Takeshita Y, Kanamori T, Nagano T, Nakagen M, Urabe T, Matsuyama N, Kaneko S, Takamura T*. Serum selenoprotein P, but not selenium, predicts future hyperglycemia in a general Japanese population. Sci Rep 2018 Nov 13;8(1)
  6. Tajima-Shirasaki N, Ishii KA, Takayama H, Shirasaki T, Iwama H, Chikamoto K, Saito Y, Iwasaki Y, Teraguchi A, Lan F, Kikuchi A, Takeshita Y, Murao K, Matsugo S, Kaneko S, Misu H, Takamura T*. Eicosapentaenoic acid down-regulates expression of the selenoprotein P gene by inhibiting SREBP-1c protein independently of the AMP-activated protein kinase pathway in H4IIEC3 hepatocytes. J Biol Chem 292:10791-10800, 2017
  7. Takayama H, Misu H, Iwama H, Chikamoto K, Saito Y, Murao K, Teraguchi A, Lan F, Kikuchi A, Saito R, Tajima N, Shirasaki T, Matsugo S, Miyamoto K, Kaneko S, Takamura T*. Metformin suppresses expression of the selenoprotein P gene via an AMP-activated kinase (AMPK)/FoxO3a pathway in H4IIEC3 hepatocytes. J Biol Chem 289:335-45, 2014
  8. Tanaka M, Saito Y, Misu H, Kato S, Kita Y, Takeshita Y, Kanamori T, Nagano T, Nakagen M, Urabe T, Takamura T, Kaneko S, Takahashi K, Matsuyama N. Development of a Sol Particle Homogeneous Immunoassay for Measuring Full-Length Selenoprotein P in Human Serum. J Clin Lab Anal 30:114-22, 2016
  9. Sugiyama M, Kikuchi A, Misu H, Igawa H, Ashihara M, Kushima Y, Honda K, Suzuki Y, Kawabe Y, Kaneko S, Takamura T. Inhibin βE (INHBE) is a possible insulin resistance-associated hepatokine identified by comprehensive gene expression analysis in human liver biopsy samples. PLOS ONE 13:e0194798, 2018
  10. Misu H, Ishikura K, Kurita S, Takeshita Y, Ota T, Saito Y, Takahashi K, Kaneko S, Takamura T*. Inverse correlation between serum levels of selenoprotein P and adiponectin in patients with type 2 diabetes. PLOS ONE 7:e34952, 2012
  11. Iwakami S, Misu H, Takeda T, Sugimori M, Matsugo S, Kaneko S, Takamura T*. Concentration-dependent dual effects of hydrogen peroxide on insulin signal transduction in H4IIEC hepatocytes. PLoS ONE 6:e27401, 2011
  12. Hellwege JN, Palmer ND, Ziegler JT, Langefeld CD, Lorenzo C, Norris JM, Takamura T, Bowden DW. Genetic variants in selenoprotein P plasma 1 gene (SEPP1) are associated with fasting insulin and first phase insulin response in Hispanics. Gene 534:33-9, 2014
  13. Lan F, Misu H, Chikamoto K, Takayama H, Kikuchi A, Mohri K, Takata N, Hayashi H, Matsuzawa-Nagata N, Takeshita Y, Noda H, Matsumoto Y, Ota T, Nagano T, Nakagen M, Miyamoto KI, Takatsuki K, Seo T, Iwayama K, Tokuyama K, Matsugo S, Tang H, Saito Y, Yamagoe S, Kaneko S, Takamura T*. LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance. Diabetes 63:1649-64, 2014
  14. Kato K, Takamura T* (co-first author), Takeshita Y, Ryu Y, Misu H, Ota T, Tokuyama K, Nagasaka S, Matsuhisa M, Matsui O, Kaneko S. Ectopic fat accumulation and distant organ-specific insulin resistance in Japanese people with nonalcoholic fatty liver disease. PLOS ONE 9:e92170, 2014
  15. Takeshita Y, Takamura T* (co-first author), Honda M, Kita Y, Zen Y, Kato K, Misu H, Ota T, Nakamura M, Yamada K, Sunagozaka H, Arai K, Yamashita T, Mizukoshi E, Kaneko S. The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial. Diabetologia 57:878-90, 2014
  16. Otoda T, Takamura T* (co-first author), Misu H, Ota T, Murata S, Hayashi H, Takayama H, Kikuchi A, Kanamori T, Shima KR, Lan F, Takeda T, Kurita S, Ishikura K, Kita Y, Iwayama K, Kato KI, Uno M, Takeshita Y, Yamamoto M, Tokuyama K, Iseki S, Tanaka K, Kaneko S. Proteasome Dysfunction Mediates Obesity-Induced Endoplasmic Reticulum Stress and Insulin Resistance in the Liver. Diabetes 62:811-24, 2013
  17. Takamura T*, Misu H, Matsuzawa-Nagata N, Sakurai M, Ota T, Shimizu A, Kurita S, Takeshita Y, Ando H, Honda M, Kaneko S. Obesity upregulates genes involved in oxidative phosphorylation in livers of diabetic patients. Obesity (Silver Spring). 16:2601-9, 2008
  18. Nakamura S, Takamura T*, Matsuzawa-Nagata N, Takayama H, Misu H, Noda H, Nabemoto S, Kurita S, Ota T, Ando H, Miyamoto K, Kaneko S. Palmitate Induces Insulin Resistance in H4IIEC3 Hepatocytes through Reactive Oxygen Species Produced by Mitochondria. J Biol Chem 284:14809-14818, 2009
  19. Matsuzawa N, Takamura T*, Kurita S, Misu H, Ota T, Ando H, Yokoyama M, Honda M, Zen Y, Nakanuma Y, Miyamoto K, Kaneko S. Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet. Hepatology 46:1392-1403, 2007
  20. Misu H, Takamura T*, Matsuzawa N, Shimizu A, Ota T, Sakurai M, Ando H, Arai K, Yamashita T, Honda M, Yamashita T, Kaneko S. Genes involved in oxidative phosphorylation are coordinately upregulated with fasting hyperglycaemia in livers of patients with type 2 diabetes. Diabetologia 50:268-277, 2007
  21. Takamura T, Sakurai M, Ota T, Ando H, Honda M, Kaneko S. Genes for systemic vascular complications are differentially expressed in the livers of type 2 diabetic patients. Diabetologia 47:638-647, 2004